Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23][CH2:24]C.C(I)CC>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][C:15]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCc2coc(-c3ccccc3)n2)cc1
Reactant: [Li]CCCC
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1CCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
4-(2-Benzyloxyethyl)-2-phenyloxazole (670 mg, 239 mmol) was dissolved in THF (10 mL) and cooled to −78° C. before adding n-butyllithium (1.15 mL of a 2.5 M solution in hexanes). The resulting orange solution was warmed to −65° C., stirred 45 min, and then propyl iodide (1.22 g, 7.17 mmol, 0.70 mL) was added via syringe. The solution was warmed to ambient temperature and stirred 90 min. The mixture was concentrated and the product purified by flash chromatography (100 mL SiO2, hexanes to 20% EtOAc/hexanes) and obtained as a colorless oil (340 mg, 44%): Rf=0.49 in 20% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.00-7.96 (m, 2H), 7.42-7.26 (m, 8H), 4.54 (s, 2H), 3.76 (t, J=7.0 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H) 1.68 (sextet, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 59 %

Procedure:
As described for example 116e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (107 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (72 mg, 59%) which was obtained as a white solid. MS: m/e=410.1 [M+H]−.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.O>CN(C=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 95.3 %

Procedure:
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60% NaH in oil (20.02 g, 0.50 mol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml). The mixture was then stirred at room temperature overnight. Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml). The filtrate, now containing more solid, was refiltered and washed with petroleum ether. The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95%) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.19 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:18])[NH:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:24][CH2:25]Br>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:10][N:9]1[CH2:25][CH2:24][N:7]([CH2:6][CH2:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])[C:8]1=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: COC(CCCNC(=O)NOCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(CCCN1CCN(OCc2ccccc2)C1=O)OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 3-(4,4-dimethoxy-butyl)-1-(benzyloxy)-urea (4.14 g, 14.7 mmol) in DMF (40 mL) was added NaH (60 wt % in mineral oil, 0.659 g, 16.5 mmol). After 30 minutes, 1,2-dibromoethane (1.30 mL, 15.1 mmol) was added and the mixture was stirred for an additional 40 minutes. An additional amount of NaH (60 wt % in mineral oil, 0.636 g, 15.9 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (150 mL), washed with brine (5×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (1:1 hexanes-EtOAc) provided 1.61 g (36%) of 1-Benzyloxy-3-(4,4-dimethoxy-butyl)-imidazolidin-2-one as a colorless oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(C)=O)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (5.56 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate:acetone) to give (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 93%) as a colored syrup: 1H NMR (CDCl3): δ 7.96–7.59 (m, 3H), 7.53 (d, 1H), 7.23 (dd, 1H), 6.93 (d, 2H), 5.97–5.94 (m, 2H), 5.07 (d, 1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.0–2.3 (b, 6H), 2.07 (m, 2H), 1.76–1.60 (m, 2H); MS m/z 405 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])(F)F)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS([C:37]1C2C(=CC=CC=2)N[N:38]=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:37]=[N:38][C:14]([F:17])=[CH:13][CH:12]=3)[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: FC(F)(F)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2-c2ccc(F)nc2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 3-1 by using 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl 1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:14](C1C=CC(B(O)O)=CC=1)#[N:15].CCOC(C)=O.[C:31]1(C)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.C([O-])([O-])=O.[Na+].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:13]1[CH:2]=[CH:3][C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH:12]=1)#[N:15]
Reactant: Cc1ccccc1
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1cc(C#N)ccc1-c1ccccc1

Procedure:
820 mg (3.4 mmol) of methyl 4-bromocinnamate were dissolved in 7 ml of dry toluene, added with 116 mg (0.1 mmol) of Pd(PPh3)4, a solution of 374 mg (1.1 mmol) of 4-cyanobenzeneboronic acid in 2 ml of MeOH, 6.8 ml of 2M Na2CO3 in water, and refluxed 9 h. Addition of EtOAc, washing with water, then with brine, filtration and flash chromatography (Merck silicagel) with Hexane/EtOAc mixtures 9/1 gave 273 mg of methyl 3-(4-cyanobiphenylyl)acrylate, mp. 150-152° C.
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].C(O)(=O)C.C(N)=[NH:18]>O>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][N:2]=[CH:1][N:18]=1
Reactant: N=CN
Reactant: COC(OC)C(=O)/C=C/N(C)C
Solvent: O
Solvent: CC(=O)O
Product: COC(OC)c1ccncn1
Temperature: 120 °C
Yield: 70.3 %

Procedure:
A mixture of (E)-4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (49.6 g, 286 mmol) and formamidine acetate (44.7 g, 429 mmol) was heated at 120° C. for 4 h. After cooling to room temperature the mixture was poured into water and extracted with dichloromethane. The combined organic extracts were then dried over sodium sulfate, filtered and evaporated. Purification by distillation afforded the title product (31 g, 70%) as a colourless liquid. Bp 59-60° C. at 1.3 mbar. MS: m/e=155.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:2][CH2:3][C:4]#[CH:5].[OH-].[K+]>Cl.C(O)C>[CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CCCCc1c2c(nn1CCC)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 0.400 g, 0.812 mmol) in 6 M HCl in ethanol (3 mL) was heated at 60° C. for 1.7 hours. The solution was allowed to cool to room temperature, and then was concentrated under reduced pressure to yield an oil. The oil was treated with 1 M aqueous potassium hydroxide to generate a white precipitate, which was isolated by filtration. The crude product was purified by chromatography (silica gel, gradient elution with 5-10% CMA in chloroform) followed by crystallization from hexanes/ethyl acetate to afford 0.061 g of 1-pent4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white crystals, mp 144.0-145.0° C.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]2[N:26]([CH:27]=1)[CH:25]=[CH:24][CH:23]=[CH:22]2.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[CH3:18][C:19]1[CH:20]=[C:21]2[N:26]([C:27]=1[C:11]([CH:9]1[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]1)=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Cc1cc2ccccn2c1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc2ccccn2c1C(=O)C1CCc2nc[nH]c2C1
Temperature: 85 °C
Yield: 38.5 %

Procedure:
To a solution of 0.50 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride and 0.39 g of 2-methylindolizine in 5 ml of 1,2-dichloroethane was added dropwise 0.90 g of phosphorus oxychloride. The reaction mixture was refluxed at 85° C. for one night. After cooling to room temperature, 5 ml of water was added thereto. The organic layer was removed, and 10 ml of chloroform was added to the aqueous layer. The solution was adjusted to a pH of 9 with a 20% aqueous solution of sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography using chloroform/methanol as an eluent, followed by recrystallization from ethanol to obtain 0.21 g of 5-[(2-methylindolizin-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:25](OCCC(C)C)=O.C(Cl)(Cl)[Cl:34]>>[ClH:34].[NH:1]1[C:2]2[C:11](=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[N:25]1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1cccc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc2cn[nH]c12
Product: Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of the ester (17.5 g, 106 mmol) in chloroform (300 mL) was added acetic anhydride (22.6 mL, 239 mmol, 2.3 eq) while maintaining the temperature below 40° C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (3.00 g, 30.6 mmol, 0.3 eq) and isoamyl nitrite (30.6 mL, 228 mmol, 2.2 eqiv) was added. The reaction mixture was heated at reflux for 24 h and was allowed to cool to room temperature. The reaction mixture was washed with a saturated, aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue and the mixture was maintained for 18 h at rt. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filteration, washed with ethyl acetate (20 mL), and dried to provide 15.3 g (68%) of methyl 1H-indazole-7-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M++1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1)[CH3:5].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[CH2:3][CH2:2][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=1
Reactant: COc1cc(OC)cc(C(C)CCBr)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: COc1cc(OC)cc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
The 3-(3,5-dimethoxyphenyl)butyltriphenylphosphonium bromide is prepared by refluxing a mixture of 1-bromo-3-(3,5-dimethoxyphenyl)butane (21.5 g., 78.5 mmoles) and triphenyl phosphine (20.5 g., 78.5 mmoles) in xylene (60 ml.) for 18 hours. The reaction mixture is then cooled to room temperature and filtered. The filter cake is washed with ether and dried in a vacuum desicator to give 36.4 g. (86%) yield of product; m.p. 190°-200° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:43][C@@H:44]([CH3:60])[CH2:45][N:46]1[CH:50]=[CH:49][C:48]([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[CH:52]=2)=[N:47]1>C(Cl)Cl.CN(C=O)C>[Cl:59][C:53]1[CH:52]=[C:51]([C:48]2[CH:49]=[CH:50][N:46]([CH2:45][C@@H:44]([NH:43][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:9][N:8]=3)=[O:12])[CH3:60])[N:47]=2)[CH:58]=[CH:57][C:54]=1[C:55]#[N:56]
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515 mmol) and DIPEA (0.090 ml, 0.515 mmol) were dissolved in 5 ml of dry DCM. Anhydrous HOBt (0.070 g, 0.515 mmol), and EDCI (0.099 g, 0.515 mmol) were added. After stirring at RT for 30 min the (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.112 g, 0.430 mmol) dissolved in 1 ml of dry DMF was added to the reaction mixture. After overnight stirring at RT a mixture of 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylic acid (0.088 g, 0.515 mmol), DIPEA (0.090 ml, 0.515 mmol), anhydrous HOBt (0.070 g, 0.515 mmol) and EDCI (0.099 g, 0.515 mmol) dissolved in 5 ml of dry DCM was added to the reaction mixture. After 3 h the solvents were evaporated and the residue was purified by CombiFlash using MeOH in DCM as an eluent. Product fractions were combined and evaporated to give 58 mg of the product. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.65 (s, 6H), 4.26 (m, 1H), 4.43 (m, 1H), 4.58 (m, 1H), 6.60 (s, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.07 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:27]([O:29]CC)=O)[C:22]([O:24]CC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:29])[CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:24]
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reactant: NCCCCN
Product: NCCCCNC(=O)C(CCCCCCOCc1ccccc1)C(=O)NCCCCN
Temperature: 90 °C

Procedure:
To a large excess of 1,4-diaminobutane (85 g, 0.964 mol) at 90° C. under argon was slowly added (over 2 hours) B2 (10.50 g, 0.030 mol). The solution was heated at 90° C. overnight and the excess diamine distilled off under reduced pressure (0.1 mbar, 28° C.) to quantitatively yield the title compound as a pale yellow low melting point solid: C24H42N4O3 requires 434. Found DCl: M+ +1 435. I.R. 1664 cm−1 (CO2). δH (CDCl3) 1.15-1.40 (10H, br m, (CH2)3CH2CH, NH2), 1.40-1.60 (10H, br m, (CH2)2CH2NH2, CH2CH2O), 1.76 (2H, q, CH2CH), 2.63 (4H, t, CH2NH2), 2.93 (2H, t, CH2CH), 3.16 (4H, q, CH2NH), 3.37. (2H, t, CH2OCH2Ph), 4.42 (2H, s, CH2Ph), 7.26 (5H, m, Ph), 7.61 (2H, t, CONH). δC (CDCl3) 25.7 (1C, CH2(CH2)2CH), 26.6 (2C, CH2CH2NH2), 28.8, 29.4 (2C, CH2CH2CH, CH2CH2O), 30.6 (2C, CH2CH2NH), 32.7 (1C, CH2CH), 39.0 (2C, CH2NHCO), 41.4 (2C, CH2NH2), 54.7 (1C, CHCO), 70.1, 72.6 (2C, CH2OCH2), 127.2 (1C, CH(CH)2C), 127.3 (2C, CHC), 128.0 (2C, CHCHC), 138.5 (1C, CCH2O), 171.0 (2C, CONH).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][OH:4].C(O)CCCCCCCCC/C=C\CC.Br[C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1.ClC1OC(C(O)=O)=CC=1>>[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][O:4][C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCC(C)CO
Agent: CC/C=C\CCCCCCCCCCO
Agent: O=C(O)c1ccc(Cl)o1
Product: CCCCCCCCCCCCC(C)COc1ccc(C(=O)O)o1

Procedure:
In the procedure of Example 4(A), 2-methyltetradecanol was substituted for cis-11-tetradecenol and 5-bromo-2-furoic acid substituted for 5-chloro-2-furoic acid to yield 5-(2-methyltetradecyloxy)-2-furancarboxylic acid, M.P. 88°-90° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Br-:9].[Br-].O1CCOCC1>CCOCC>[Br:9][C:6]1[CH:5]=[C:3]([OH:4])[C:1](=[CH:8][CH:7]=1)[OH:2]
Reactant: Oc1ccccc1O
Reactant: [Br-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Oc1ccc(Br)cc1O

Procedure:
Catechol (11.0 g; 0.100 mol) is dissolved in 50 ml of ether and 29 g of freshly-prepared dioxane dibromide (Yanovskaya, Terent'ev and Belsn'kii), J. Gen. Chem. Vol. 22:1594 (1952)) is added slowly as a solution in 50 ml of ether. The organic solution is washed with water (3 times) and dried over MgSO4. The solvent is removed under reduced pressure to yield 4-bromocatechol as a red-brown oil. 1H NMR δ 5.52 (s, 1), 5.70 (s, 1), 6.74 (d, 1, J=8.74 Hz), 6.92 (dd, 1, J=8.3, 2.3 Hz), and 7.01 ppm (d, 1, J=2.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.BrCCBr.[Mg].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:14][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of m-chlorotoluene (12.66 g, 0.100 mol) and 1,2-dibromoethane (0.5 ml) in THF (20 ml) was added to magnesium turnings (2.67 g, 0.110 mol). The mixture was heated under reflux for 4 h, after which the heating bath was removed and trimethylchlorosilane (11.08 g, 0.102 mol) was added so that gentle reflux was maintained. The mixture was stirred for another 0.5 h and 5% NaHCO3 (100 ml) was then added. The resulting mixture was extracted with CH2Cl2 (3×50 ml), the organic phase was washed with brine and dried (MgSO4). Filtration and evaporation provided 15.05g (92%) of 36 as a pale yellow liquid. Spectroscopic data were identical to those previously reported in the literature.40
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3C(CN4C(=O)C5=CC=CC=C5C4=O)=CN=[C:12]3[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:8]=2[CH:36]=1)([O-])=O.O.[NH2:38]N.[CH2:40](O)[CH3:41]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:9]1[N:10]2[C:41]3[CH:40]=[CH:36][CH:4]=[CH:5][C:6]=3[CH:7]=[N:13][CH2:12][C:11]2=[N:38][CH:8]=1
Reactant: CCO
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2
Solvent: O
Product: Clc1ccccc1-c1cnc2n1-c1ccccc1C=NC2

Procedure:
In the manner given in Example 28, 8-nitro-1-(phthalimidomethyl)-6-(o-chlorophenyl)-4H-imidazo[1,2 -a][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol to give 8-nitro-1-(aminomethyl)-6 -(o-chlorophenyl-4H-imidazo[1,2-a][1,4]-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[CH3:15][N:16]=[C:17]=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:17](=[O:18])[NH:16][CH3:15]
Reactant: CN=C=O
Reactant: CC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Product: CNC(=O)Oc1c(Cl)cc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 21.5 grams (0.1 mole) 3'-chloro-4'-hydroxy-5'-nitroacetophenone and 85.0 milliliters (a large excess) of methylisocyanate was refluxed for 5 hours. On cooling, a white crystalline product was formed. The product was filtered (weight 18.0 grams, melting point 115°-118° C.) and was identified by characteristic peaks in the infrared spectrum as 3'-chloro-4'-(N-methylcarbamoyloxy)-5'-nitroacetophenone.